PII-169 - EVALUATION OF THE POTENTIAL IMPACT ON PHAMACOKINETICS OF VARIOUS CYTOCHROME P450 SUBSTRATES OF INCREASING IL-6 LEVELS FOLLOWING ADMINISTRATION OF THE T-CELL BISPECIFIC ENGAGER GLOFITAMAB

N. Parrott¹, N. DJEBLI²; ¹F Hoffmann LaRoche, Roche Pharmaceutical Research and Early Development, Basel, Switzerland, ²Luzsana Biotechnonology (subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd), Luzsana Biotechnonology (subsidiary of Jiangsu Hengrui Pharmaceuticals Co., Ltd).

Background: Glofitamab is a novel T cell bispecific (TCB) antibody developed for the treatment of R/R DLBCL and other NHL indications. By simultaneously binding to human CD20-expressing tumor cells and the CD3 antigen of the T-cell receptor (TCR) on T cells, glofitamab induces tumor cell lysis, in addition to T-cell activation, proliferation and cytokine release. Here, we describe PBPK modeling performed to assess the potential impact of glofitamab-associated transient increases in IL-6 on the pharmacokinetics of several CYP substrates.

Methods: By refinement of a previously described IL-6 model and inclusion of in vitro CYP suppression data for CYP3A4, CYP1A2 and 2C9, a PBPK model was established in the Simcyp® Simulator to capture the induced IL6 levels seen when glofitamab is administered at the intended dose and dosing regimen. Following model qualification, the PBPK model was used to predict the potential impact of CYP suppression on exposures of various CYP probe substrates.

Results: PBPK analysis predicted that, in the worst-case, the transient elevation of IL-6 would increase exposures of CYP3A4, CYP2C9 and CYP1A2 substrates by less than or equal to twofold. CYP3A4 was the most sensitive CYP isoform. Increases for CYP3A4, CYP2C9 and CYP1A2 substrates were projected to be 1.75, 1.19 and 1.09-fold following the first administration and 2.08, 1.28 and 1.49-fold following repeated administrations.

Conclusion: It is recommended that there are no restrictions on concomitant treatment with any other drugs. Consideration may be given for potential DDI during the first cycle in patients who are receiving concomitant CYP substrates with a narrow therapeutic index via monitoring for toxicity (e.g., warfarin) or for drug concentrations (e.g., cyclosporine).